The de novo DNA methyltransferase DNMT3B plays an important role in multiple myeloma cell growth, clonogenicity and drug response

Multiple myeloma (MM) is an incurable plasma cell malignancy due to the development of drug resistance (DR). In about half of the MM patients, modifications are observed in epigenetic modifiers (epiplayers) at the time of diagnosis and this further increases at relapse, indicating an important role for epiplayers in MM cell DR. However, so far, only for two epiplayers, MMSET and EZH2, a clear role in MM cell DR development has been established. We recently found that the expression of the de novo DNA methyltransferase 3B (DNMT3B) is significantly increased in relapsed MM patients and that high DNMT3B mRNA expression correlates with a worse disease outcome in both newly diagnosed and relapsed patients, indicating a role for DNMT3B in MM progression and DR. Targeting DNMT3B using either the DNMT3B specific inhibitor Nanaomycin A or genetic inhibition showed potent anti-MM effects, including a strong decrease in cell proliferation and an increase in cell death. Furthermore, in line with its presumed role in cancer cell stemness, DNMT3B inhibition significantly reduced the number of colonies using the colony formation assays. Importantly, Nanaomycin A also further increased the anti-clonogenic activity of the standard of care agents bortezomib and melphalan, as evidenced by a significantly further decrease in the number of colonies compared to both single agents. Together, our findings provide first evidence that DNMT3B could be a novel promising epigenetic target to overcome or delay relapse in MM. In the near future, the anti-myeloma activity of DNMT3B targeting will be validated in vivo in the murine 5TMM models and the underlying mechanisms will be determined, focusing mainly on DNA methylation patterns and gene expression profiles.